Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.

ABSTRACT: DNMT1 is an important epigenetic regulator that plays a key role in the maintenance of DNA methylation. Here we determined the crystal structure of DNMT1 in complex with USP7 at 2.9?Å resolution. The interaction between the two proteins is primarily mediated by an acidic pocket in USP7 and Lysine residues within DNMT1's KG linker. This intermolecular interaction is required for USP7-mediated stabilization of DNMT1. Acetylation of the KG linker Lysine residues impair DNMT1-USP7 interaction and promote the degradation of DNMT1. Treatment with HDAC inhibitors results in an increase in acetylated DNMT1 and decreased total DNMT1 protein. This negative correlation is observed in differentiated neuronal cells and pancreatic cancer cells. Our studies reveal that USP7-mediated stabilization of DNMT1 is regulated by acetylation and provide a structural basis for the design of inhibitors, targeting the DNMT1-USP7 interaction surface for therapeutic applications.

SUBMITTER: Cheng J

PROVIDER: S-EPMC4432644 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.

Cheng Jingdong J Yang Huirong H Fang Jian J Ma Lixiang L Gong Rui R Wang Ping P Li Ze Z Xu Yanhui Y

Nature communications 20150511

DNMT1 is an important epigenetic regulator that plays a key role in the maintenance of DNA methylation. Here we determined the crystal structure of DNMT1 in complex with USP7 at 2.9 Å resolution. The interaction between the two proteins is primarily mediated by an acidic pocket in USP7 and Lysine residues within DNMT1's KG linker. This intermolecular interaction is required for USP7-mediated stabilization of DNMT1. Acetylation of the KG linker Lysine residues impair DNMT1-USP7 interaction and pr ...[more]

PMID: 25960197

Similar Datasets

Molecular mechanism for the substrate recognition of USP7.

Project description: Not available

| S-EPMC4624675 | biostudies-literature

LINC00265 promotes colorectal tumorigenesis via ZMIZ2 and USP7-mediated stabilization of β-catenin.

Project description:Colorectal cancer (CRC) is the third most prevalent world cancer and oncogenic β-catenin is frequently dysregulated in CRC. Long noncoding RNAs (lncRNAs) play critical roles in colorectal tumorigenesis; however, the contributions of lncRNAs to human CRC remain largely unknown. In this study, we report that LINC00265 is upregulated and predicts poor clinical outcome in human patients with CRC. Depletion of LINC00265 and ZMIZ2 distinctly attenuates colorectal tumorigenesis in mice. Mechanistically, LINC00265 augments ZMIZ2 expression by acting as an endogenous sponge against several miRNAs, which directly target ZMIZ2 expression. Moreover, ZMIZ2 recruits the enzyme USP7, which deubiquitylates and stabilizes β-catenin, thereby facilitating colorectal tumorigenesis. In addition, β-catenin mediates LINC00265 and ZMIZ2 oncogenic phenotypes. Taken together, the LINC00265-ZMIZ2-β-catenin signaling axis plays a critical role in the colorectal tumorigenesis, which may be a potential therapeutic target.

| S-EPMC7206056 | biostudies-literature

Insight into the molecular mechanism behind PEG-mediated stabilization of biofluid lipases.

Project description:Bioconjugates established between anionic polyethylene glycol (PEG) based polymers and cationic proteins have proven to be a promising strategy to engineer thermostable biocatalysts. However, the enzyme activity of these bioconjugates is very low and the mechanism of non-covalent PEG-stabilization is yet to be understood. This work presents experimental and molecular dynamics simulation studies, using lipase-polymer surfactant nanoconjugates from mesophile Rhizomucor miehei (RML), performed to evaluate the effect of PEG on enzyme stability and activity. Results demonstrated that the number of hydrogen bonds between the cationized RML and PEG chain correlates with enzyme thermostability. In addition, an increase of both the number of PEG-polymers units and cationization degree of the enzyme leads to a decrease of enzyme activity. Modelling with SAXS data of aqueous solutions of the biofluid lipases agrees with previous hypothesis that these enzymes contain a core constituted of folded protein confined by a shell of surfactants. Together results provide valuable insight into the mechanism of non-covalent PEG mediated protein stabilization relevant for engineering active and thermostable biofluids. Furthermore, the first biofluids RML with activity comparable to their cationized counterpart are presented.

| S-EPMC6095910 | biostudies-literature

The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.

Project description:Aberrant DNA methylation is often associated with cancer and the formation of tumors; however, the underlying mechanisms, in particular the recruitment and regulation of DNA methyltransferases remain largely unknown. In this study, we identified USP7 as an interaction partner of Dnmt1 and UHRF1 in vivo. Dnmt1 and USP7 formed a soluble dimer complex that associated with UHRF1 as a trimeric complex on chromatin. Complex interactions were mediated by the C-terminal domain of USP7 with the TS-domain of Dnmt1, whereas the TRAF-domain of USP7 bound to the SRA-domain of UHRF1. USP7 was capable of targeting UHRF1 for deubiquitination and affects UHRF1 protein stability in vivo. Furthermore, Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo. Strikingly, when analyzing the impact of UHRF1 and USP7 on Dnmt1-dependent DNA methylation, we found that USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro. Therefore, we propose a dual role of USP7, regulating the protein turnover of UHRF1 and stimulating the enzymatic activity of Dnmt1 in vitro and in vivo.

| S-EPMC3201865 | biostudies-other

Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions.

Project description:DNA methyltransferases (DNMTs) including DNMT1 are a conserved family of cytosine methylases that play crucial roles in epigenetic regulation. The versatile functions of DNMT1 rely on allosteric networks between its different interacting partners, emerging as novel therapeutic targets. In this work, based on the modeling structures of DNMT1-ubiquitylated H3 (H3Ub)/ubiquitin specific peptidase 7 (USP7) complexes, we have used a combination of elastic network models, molecular dynamics simulations, structural residue perturbation, network modeling, and pocket pathway analysis to examine their molecular mechanisms of allosteric regulation. The comparative intrinsic and conformational dynamics analysis of three DNMT1 systems has highlighted the pivotal role of the RFTS domain as the dynamics hub in both intra- and inter-molecular interactions. The site perturbation and network modeling approaches have revealed the different and more complex allosteric interaction landscape in both DNMT1 complexes, involving the events caused by mutational hotspots and post-translation modification sites through protein-protein interactions (PPIs). Furthermore, communication pathway analysis and pocket detection have provided new mechanistic insights into molecular mechanisms underlying quaternary structures of DNMT1 complexes, suggesting potential targeting pockets for PPI-based allosteric drug design.

| S-EPMC8434485 | biostudies-literature

Cyclophosphamide perturbs cytosine methylation in Jurkat-T cells through LSD1-mediated stabilization of DNMT1 protein.

Project description:Aberrant cytosine methylation is known to be associated with cancer development. Here, we assessed how common cancer chemotherapeutic agents perturb cytosine methylation in Jurkat-T acute lymphoblastic leukemia cells. We tested six antitumor agents and found that cyclophosphamide induced the most pronounced increase in global DNA cytosine methylation after a 24-h treatment. Long-term treatment with cyclophosphamide led to a time-dependent increase in cytosine methylation level with up to 4 days of treatment, and the extent of cytosine methylation returned to normal level after 8 days. The trend of change in DNA methylation level paralleled that of the expression level of DNMT1 protein, whereas no significant increase in DNMT1 mRNA level was observed. Previous studies showed that the stability of endogenous DNMT1 protein is regulated by lysine methylation through histone lysine methyltransferase Set7 and lysine-specific demethylase 1 (LSD1), with the methylated DNMT1 being the target for proteasomal degradation. We observed that the elevated expression of DNMT1 protein at 4 days of treatment was correlated with the increased expression of LSD1 protein and with the decreased frequency of K142 methylation in DNMT1. Taken together, our results showed that cyclophosphamide perturbed temporarily global cytosine methylation in Jurkat-T cells via regulation of the lysine methylation level in DNMT1.

| S-EPMC3221796 | biostudies-literature

USP7 negatively controls global DNA methylation by attenuating ubiquitinated histone-dependent DNMT1 recruitment.

Project description:Previous studies have implicated an essential role for UHRF1-mediated histone H3 ubiquitination in recruiting DNMT1 to replication sites for DNA maintenance methylation during S phase of the cell cycle. However, the regulatory mechanism on UHRF1-mediated histone ubiquitination is not clear. Here we present evidence that UHRF1 and USP7 oppositely control ubiquitination of histones H3 and H2B in S phase of the cell cycle and that DNMT1 binds both ubiquitinated H3 and H2B. USP7 knockout markedly increased the levels of ubiquitinated H3 and H2B in S phase, the association of DNMT1 with replication sites and importantly, led to a progressive increase of global DNA methylation shown with increased cell passages. Using DNMT3A/DNMT3B/USP7 triple knockout cells and various DNA methylation analyses, we demonstrated that USP7 knockout led to an overall elevation of DNA methylation levels. Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1. Altogether our study provides evidence that USP7 is a negative regulator of global DNA methylation and that USP7 protects the genome from excessive DNA methylation by attenuating histone ubiquitination-dependent DNMT1 recruitment.

| S-EPMC7445300 | biostudies-literature

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.

Project description:The histone demethylase PHF8 has been implicated in multiple pathological disorders, including X-linked mental retardation and tumorigenesis. However, it is not clear how the abundance and function of PHF8 are regulated. Here, we report that PHF8 physically associates with the deubiquitinase USP7. Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation. The USP7-encoding gene was also transcriptionally regulated by PHF8, via positive feedback. USP7 was overexpressed in breast carcinomas, and the level of expression positively correlated with expression of PHF8 and cyclin A2 and with the histological grade of breast cancer. We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage. Moreover, USP7-promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair. Our study mechanistically links USP7 to epigenetic regulation and DNA repair. Moreover, these data support the pursuit of USP7 and PHF8 as potential targets for breast cancer intervention, especially in combination with chemo- or radiotherapies.

| S-EPMC4887182 | biostudies-literature

USP7 Promotes deubiquitination and stabilization of MyD88 to enhance immune responses.

Project description:Toll-like receptors (TLRs) are involved in the sensing of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), flagellin, unmethylated double-stranded DNA (CpG), single-stranded RNA (ssRNA) and lipoproteins. Myeloid differentiation primary response protein 88 (MyD88) is a canonical adaptor for the Toll-like receptor family which has crucial roles in host defense against infection by microbial pathogens. The dysregulation of MyD88 may also induce autoimmune diseases. Here, we demonstrate that the deubiquitinase USP7 interacts with MyD88 in chicken, with knockdown or overexpression of USP7 leading to the regulation of MyD88 protein in a positive manner. Consequently, USP7 positively regulates the expression of proinflammatory factors upon LPS challenge. Furthermore, we observed USP7-deficient mice to be more susceptible to infection by Salmonella typhimurium. Collectively, our findings demonstrate MyD88 as a bona fide substrate of USP7 and uncover a mechanism by which USP7 regulates innate immune signaling.

| S-EPMC9412818 | biostudies-literature

USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin.

Project description:Axin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.

| S-EPMC6744515 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data